Pyridinyl cyclohexanecarboxamide cooling compounds

ABSTRACT

A method of providing a cooling effect to a product includes the incorporation into the product of at least one compound of the formula I 
     
       
         
         
             
             
         
       
     
     in which m is a number between 0 and 2, X, Y and Z are selected independently from the group consisting of H, halogen, OH, Me, Et, MeO and EtO, and R 1 , R 2  and R 3  together comprise at least 6 carbons, selected such that
         (a) (i) R 1  is selected from the group consisting of H, Me, Et, isopropyl and C 4 -C 5  branched alkyl; and    (ii) R 2  and R 3  are independently selected from the group consisting of Me, Et, isopropyl and Ca-branched alkyl; or   (b) any two or all of R 1 , R 2  and R 3  together form a monocyclic, bicyclic or tricyclic radical having up to 10 carbons.       

     The compounds confer substantial cooling effects on compositions applied to the skin or taken orally, such as toothpastes, mouthwashes, foodstuffs, beverages, confectionery, tobacco products, skin creams and ointments.

The present application is a continuation of co-pending U.S. Ser. No. 11/990,103, having a 371(c) date of Sep. 16, 2009, which is a 371 of PCT/CH2006/000427, filed Aug. 14, 2006, which claims the benefit of the filing date under 35 USC §119(e) of U.S. Provisional Patent Application No. 60/708,153, filed on Aug. 15, 2005, which applications are incorporated herein by reference.

This invention relates to cooling compounds.

Cooling compounds, that is, chemical compounds that impart a cooling sensation to the skin or the mucous membranes of the body, are well known to the art and are widely used in a variety of products such as foodstuffs, tobacco products, beverages, dentifrices, mouthwashes and toiletries.

One class of cooling compounds that have enjoyed substantial success consists of N-substituted p-menthane carboxamides. Examples of these compounds are described in, for example, British Patents GB 1,351,761-2 and United States patent U.S. Pat. No. 4,150,052.

It has now been found that a particular selection of such compounds exhibits a cooling effect that is both surprisingly strong and long-lasting. A method is provided, therefore, of providing a cooling effect to a product, comprising the incorporation into the product of at least one compound of the formula I

in which m is a number between 0 and 2, X, Y and Z are selected independently from the group consisting of H, halogen, OH, Me, Et, MeO and EtO, and R¹, R² and R³ together comprise at least 6 carbons, selected such that

-   -   (a) (i) R¹ is selected from the group consisting of H, Me, Et,         isopropyl and C₄-C₅ branched alkyl; and     -    (ii) R² and R³ are independently selected from the group         consisting of Me. Et, isopropyl and Ca-branched alkyl; or     -   (b) any two or all of R¹, R² and R³ together form a monocyclic,         bicyclic or tricyclic radical having up to 10 carbons.

Me is defined as methyl, and Et is defined as ethyl.

Examples of cyclic radicals as described under (b) above include 3-para-menthyl, bornyl and adamantyl.

The compounds of formula (I) may comprise one or more chiral centres and as such may exist as a mixture of stereoisomers, or they may be resolved as isomerically pure forms. Resolving stereoisomers adds to the complexity of manufacture and purification of these compounds and so it is preferred to use the compounds as mixtures of their stereoisomers simply for economic reasons. However, if it is desired to prepare individual stereoisomers, this may be achieved according to methods known in the art, e.g. preparative HPLC and GC or by stereoselective syntheses.

In some embodiments, the compounds are those in which X, Y, Z are H, OH, Me or OMe. In certain embodiments, the compounds are those in which m is 2; X, Y and Z are H or Me and R¹, R² and R³ are taken from Table 1.

TABLE 1 Exemplary R¹, R² and R³ groups. R¹ R² R³ H bornyl H 3-p-menthyl H isopropyl isopropyl methyl isopropyl isopropyl ethyl ethyl ethyl adamantyl

A particularly effective compound is that in which R¹ is H and R² and R³ together form a 3-p-menthyl ring.

Examples of effective compounds are (1R,2S,5R)-2-isopropyl-5-methyl-N-(pyridinalkyl)cyclohexanecarboxamide and (2S,5R)-2-isopropyl-5-methyl-N-(pyridinalkyl)cyclohexanecarboxamide. Particular examples of these are (1R,2S,5R)-2-isopropyl-5-methyl-N-(2-(pyridin-4-yl)ethyl)cyclohexanecarboxamide and (2S,5R)-2-isopropyl-5-methyl-N-(2-(pyridin-4-yl)ethyl)cyclohexanecarboxamide.

Certain of the compounds are novel. A compound is therefore provided of the formula I as hereinabove described, in which m=2 and X, Y, Z, R¹, R², R³ have the meanings given hereinabove, with the proviso that when R² and R³ form a para-menthyl ring, at least one of R¹, X, Y and Z is a moiety other than H.

A compound is also provided according to formula I as hereinabove described, in which X, Y, Z, R¹ are H and R², R³ have the meanings given hereinabove.

In certain embodiments R¹ is hydrogen and R² and R³ are independently selected from the group consisting of Me, Et and C₃-C₄ branched alkyl; or R¹, R² and R³ together form a monocyclic, bicyclic or tricyclic radical having up to 10 carbons.

The compounds may be easily prepared and isolated by art-recognized methods.

They are distinguished from similar compounds of the prior art by their surprisingly high cooling effect (up to 100 times higher than that of similar known compounds) and by the longevity of the cooling effect. These compounds also have a high solubility in oily solvents, such as mint oils, and acidic aqueous solutions, such as soft drinks. These features expand the uses of cooling compounds to a larger variety of products.

The compounds may be used in products that are applied to the mouth or the skin to give a cooling sensation. By “applying” is meant any form of bringing into contact, for example, oral ingestion or, in the case of tobacco products, inhalation. In the case of application to the skin, it may be, for example, by including the compound in a cream or salve, or in a sprayable composition. There is also provided, therefore, a method of providing a cooling effect to the mouth or skin by applying thereto a product comprising a compound as hereinabove described.

The range of products in which the compounds may be used is very wide, and it includes by way of example only, dentifrices such as toothpaste and toothgel, mouthwashes, foodstuffs, beverages, confectionery, tobacco products, skin creams and ointments, both cosmetic and medicinal.

The compounds may be used alone or in combination with other cooling compounds known in the art, e.g., menthol, menthone, isopulegol, N-ethyl p-menthanecarboxamide (WS-3), N,2,3-trimethyl-2-isopropylbutanamide (WS-23), menthyl lactate (Frescolat™ ML), menthone glycerine acetal (Frescolat™ MGA), mono-menthyl succinate (Physcool™), mono-menthyl glutarate, O-menthyl glycerine (CoolAct™ 10), menthyl-N,N-dimethylsuccinamate and 2-sec-butylcyclohexanone (Freskomenthe™).

Certain embodiments are now further described by means of the following non-limiting examples.

EXAMPLE 1 Preparation of N-(4-pyridinyl) p-menthanecarboxamide [(1R,2S,5R)-2-isopropyl-5-methyl-N-(2-(pyridin-4-yl)ethyl)cyclohexanecarboxamide]

To a flask are added 4.7 g (50 mmol) of pyridin-4-ylamine, 4.04 mL of pyridine and 100 mL MtBE. To this mixture, 10 g of p-menthanecarboxyl chloride are added dropwise over 5 minutes. The reaction mixture is stirred for 24 hours. To the reaction mixture, 50 mL of water are added. The mixture is separated. The organic layer is washed with 50 mL of water and 50 mL of brine. The organic layer is dried over MgSO₄. The solvent is evaporated in vacuo to afford the crude product, which is recrystallized from hexanes to afford 6.2 g of the desired product with the following spectroscopic properties:

MS: 260 ([M^(+·)]), 217, 149, 121, 95

¹H NMR (300 MHz; CDCl₃) δ: 8.49 (d, 2H), 7.77 (s, 1H), 7.52 (d, 2H), 2.22 (td, 1H), 1.9 (broad d, 2H), 1.85-1.57 (m, 3H), 1.44-1.22 (m, 2H), 1.16-0.99 (m, 2H), 0.94 (d, 3H), 0.91 (d, 3H), 0.81 (d, 3H)

¹³C NMR (75 MHz; CDCl₃) δ: 175.4, 150.5, 145.0, 113.4, 50.7, 44.3, 39.25, 34.3, 32.1, 28.7, 23.7, 22.1, 21.2, 16.1

EXAMPLE 2 Preparation of N-(2-pyridin-2-ylethyl) p-menthanecarboxamide [(1R,2S,5R)-2-isopropyl-5-methyl-N-(2-(pyridin-2-yl)ethyl)cyclohexanecarboxamide]

A preparation similar to that described in example 1 gives the desired product with the following spectroscopic properties:

MS: 288 ([M^(+·)]), 273, 245, 149, 121, 95

¹H NMR (300 MHz; DMSO) δ: 8.53 (d, 1H), 7.62 (td, 1H), 7.16 (m, 2H), 6.43 (s, 1H), 3.67 (nontuplet, 2H), 3.00 (t, 2H), 1.95 (td, 1H), 1.84-1.53 (m, 4H), 1.47 (broad t, 1H), 1.4-1.1 (m, 2H), 0.87 (d, 3H), 0.84 (d, 3H), 0.66 (d, 3H)

¹³C NMR (75 MHz; DMSO) δ: 175.8, 159.7, 148.9, 136.7, 123.6, 121.55, 49.8, 44.3, 39.4, 38.35, 36.9, 34.6, 32.3, 28.55, 23.9, 22.3, 21.3, 15.95

EXAMPLE 3 Preparation of 2-isopropyl-2,3-dimethyl-N-(2-(pyridin-2-yl)ethyl)butanamide

A preparation similar to that described in example 1, using 2-isopropyl-2,3-dimethylbutanoyl chloride, gives the desired product with the following spectroscopic properties:

MS: 262 ([M+]), 220, 205, 149, 121, 106, 93

¹H NMR (300 MHz; CDCl3) 8.53 (d, 1H), 7.63 (t, 1H), 7.16 (m, 2H), 6.69 (s, 1H), 3.67 (dd, 2H), 2.99 (t, 2H), 1.96 (m, 2H), 0.96 (s, 3H), 0.85 (d, 6H), 0.79 (d, 6H)

13C (75 MHz; CDCL3) 175.6, 160.0, 149.1, 136.6, 123.4, 121.5, 51.4, 38.4, 36.9, 32.6, 18.1, 17.4, 14.1

EXAMPLE 4 Assessment of Cooling Effect

A small group of panelists is asked to taste various aqueous solutions of cooling compounds and indicate which solutions had a cooling intensity similar or slightly higher than that of a solution of menthol at 2 ppm. The same panel is asked to taste these solutions at the chosen concentrations and to record the cooling intensity at regular time intervals until no cooling could be sensed in the mouth. The results are shown in Table 2.

TABLE 2 Experiments on cooling intensity and longevity. Chemical Concentration Longevity l-Menthol 2.0 ppm 35 minutes N-ethyl p-menthanecarboxamide (WS-3) 1.5 ppm 57 minutes Formula I, m = 0, X = Y = Z = R1 = H, 0.5 ppm 50 minutes R2 + R3 = p-menthyl (compound of Example 1) Formula I, m = 2, X = Y = Z = R1 = H, 0.02 ppm 60 minutes R2 + R3 = p-menthyl (compound of example 2) Formula I, m = 2, X = Y = Z = H, 0.4 ppm R1 = methyl, R2 = R3 = isopropyl (compound of example 3)

From Table 2, it can be seen that the compounds of Formula I are up to 100 times stronger and last longer than menthol, the reference cooling compound. Compounds of Formula I are also much stronger than WS-3, the best cooling compound of the prior art.

In a second experiment, the same panel is asked to taste various solutions of compounds having various concentrations and to indicate which of these solutions had a cooling intensity similar to or slightly higher than that of a solution of menthol at 2 ppm. This is the “isointensive concentration”. The results are shown in Table 3.

TABLE 3 Intensity of compounds where R² + R³ = p-menthane and R¹ = X = Y = Z = H Value of m Position of main Isointensive (Chain length) moiety on ring concentration 0 2 or 6 0.2 ppm 0 3 or 5 0.4 ppm 0 4 0.5 ppm  1* 2 or 6* 0.67 ppm 1 3 or 5 0.25 ppm 1 4 0.2 ppm 2 2 or 6 0.02 ppm 2 3 or 5 0.004 ppm  2**  4** 0.05 ppm *compound of Example 1 **compound of Example 2

From Table 2 and 3, it can be seen that compounds of Formula I with various chain lengths and substitution patterns all have lower usage levels than the reference cooling chemicals, menthol and WS-3.

EXAMPLE 5 Application in Mouthwash

Alcohol 95% 177 mL Sorbitol 70% 250 g Compound of example 1 as a 50 mL 1% solution in alcohol Peppermint oil, Terpeneless 0.300 g Methyl salicylate 0.640 g Eucalyptol 0.922 g Thymol 0.639 g Benzoic acid 1.500 g Pluronic ™ F127 nonionic surfactant 5.000 g Sodium Saccharin 0.600 g Sodium Citrate 0.300 g Citric Acid 0.100 g Water q.s. 1 liter

All the ingredients are mixed. 30 mL of obtained solution is put in the mouth, swished around, gargled and spit out. An icy-cool sensation is felt in every area of the mouth as well as lips.

EXAMPLE 6 Application in Toothpaste

Opaque toothgel 97.000 g Compound of example 2 as a 2% 2.500 g solution in propylene glycol Peppermint oil, Terpeneless 0.500 g

The chemicals are mixed in the toothgel, a piece of toothgel is put on a toothbrush and a panelist's teeth are brushed. The mouth is rinsed with water and the water is spit out. An intense cooling sensation is felt by the panelist in all areas of the mouth.

EXAMPLE 7 Application in Beverages

1.5 mg of the compound of example 2 is dissolved in a 355 mL (12 fl oz.) can of clear lemon/lime soda. A panelist experiences an agreeable delayed cooling sensation in the mouth with no throat burning. No unpleasant after-taste is observed.

Although the invention has been described in detail through the above detailed description and the preceding examples, these examples are for the purpose of illustration only and it is understood that variations and modifications can be made by one skilled in the art without departing from the spirit and the scope of the invention. It should be understood that the embodiments described above are not only in the alternative, but can be combined. 

1. A method of providing a cooling effect to a product, comprising the incorporation into the product of at least one compound of the formula I

in which m is a number between 0 and 2, X, Y and Z are selected independently from the group consisting of H, halogen, OH, Me, Et, MeO and EtO, and R¹, R² and R³ together comprise at least 6 carbons, selected such that (a) (i) R¹ is selected from the group consisting of H, Me, Et, isopropyl and C₄-C₅ branched alkyl; and  (ii) R² and R³ are independently selected from the group consisting of Me, Et, isopropyl and C₄-branched alkyl; or (b) any two or all of R¹, R² and R³ together form a monocyclic, bicyclic or tricyclic radical having up to 10 carbons.
 2. The method according to claim 1, in which X, Y, and Z are independently selected from H, OH, Me and OMe.
 3. The method according to claim 1, in which m is 2; X, Y and Z are independently selected from H and Me and R¹, R² and R³ are selected according to the following table: R¹ R² R³ H bornyl H 3-p-menthyl H isopropyl isopropyl methyl isopropyl isopropyl ethyl ethyl ethyl adamantyl


4. The method according to claim 1, wherein R¹ is hydrogen and R² and R³ are independently selected from the group consisting of Me, Et and C₃-C₄ branched alkyl.
 5. The method according to claim 1, wherein R¹, R² and R³ together form a monocyclic, bicyclic or tricyclic radical having up to 10 carbons.
 6. The method according to claim 1, wherein the compound of formula I is used in combination with at least one other cooling compound comprising menthol, menthone, isopulegol, N-ethyl p-menthanecarboxamide, N,2,3-trimethyl-2-isopropylbutanamide, menthyl lactate, menthone glycerine acetal, mono-menthyl succinate, mono-menthyl glutarate, O-menthyl glycerine, menthyl-N,N-dimethylsuccinamate, or 2-sec-butylcyclohexanone.
 7. A product adapted to be applied to the skin or taken orally, comprising at least one compound according to the formula I

in which m is a number between 0 and 2, X, Y and Z are selected independently from the group consisting of H, halogen, OH, Me, Et, MeO and EtO, and R¹, R² and R³ together comprise at least 6 carbons, selected such that (a) (i) R¹ is selected from the group consisting of H, Me, Et, isopropyl and C₄-C₅ branched alkyl; and  (ii) R² and R³ are independently selected from the group consisting of Me, Et, isopropyl and Ca-branched alkyl; or (b) any two or all of R¹, R² and R³ together form a monocyclic, bicyclic or tricyclic radical having up to 10 carbons.
 8. The product according to claim 7, wherein X, Y, and Z are independently selected from H, OH, Me and OMe.
 9. The product according to claim 7, wherein m is 2; X, Y and Z are independently selected from H and Me and R¹, R² and R³ are selected according to the following table: R¹ R² R³ H Bornyl H 3-p-menthyl H Isopropyl isopropyl methyl Isopropyl isopropyl ethyl Ethyl ethyl adamantyl


10. The product according to claim 7, wherein R¹ is hydrogen and R² and R³ are independently selected from the group consisting of Me, Et and C₃-C₄ branched alkyl.
 11. The product according to claim 7, wherein R¹, R² and R³ together form a monocyclic, bicyclic or tricyclic radical having up to 10 carbons.
 12. The product according to claim 7, wherein the product is used in combination with at least one other cooling compound comprising menthol, menthone, isopulegol, N-ethyl p-menthanecarboxamide, N,2,3-trimethyl-2-isopropylbutanamide, menthyl lactate, menthone glycerine acetal, mono-menthyl succinate, mono-menthyl glutarate, O-menthyl glycerine, menthyl-N,N-dimethylsuccinamate, or 2-sec-butylcyclohexanone.
 13. A compound of Formula I

in which m=2 and X, Y and Z are selected independently from the group consisting of H, halogen, OH, Me, Et, MeO and EtO, and R¹, R² and R³ together comprise at least 6 carbons, selected such that (a) (i) R¹ is selected from the group consisting of H, Me, Et, isopropyl and C₄-C₅ branched alkyl; and  (ii) R² and R³ are independently selected from the group consisting of Me, Et, isopropyl and Ca-branched alkyl; or (b) any two or all of R¹, R² and R³ together form a monocyclic, bicyclic or tricyclic radical having up to 10 carbons; with the proviso that, when R² and R³ form a para-menthyl ring, at least one of R¹, X, Y and Z is a moiety other than H.
 14. The compound according to claim 13, wherein m is 2; X, Y and Z are independently selected from H and Me and R¹, R² and R³ are selected according to the following table: R¹ R² R³ H bornyl H 3-p-menthyl H isopropyl isopropyl methyl isopropyl isopropyl ethyl ethyl ethyl adamantyl


15. The method according to claim 1, wherein in the at least one compound of formula I, m is 1, X, Y and Z are H, R¹ is H, and R² and R³ together form 3-p-menthyl.
 16. The method according to claim 1, wherein in the at least one compound of formula I, m is 2, X is Me, Y and Z are H, R¹ is H, and R² and R³ together form 3-p-menthyl.
 17. The product according to claim 7, wherein in the at least one compound of formula I, m is 1, X, Y and Z are H, R¹ is H, and R² and R³ together form 3-p-menthyl.
 18. The product according to claim 7, wherein in the at least one compound of formula I, m is 2, X is Me, Y and Z are H, R¹ is H, and R² and R³ together form 3-p-menthyl.
 19. The compound according to claim 13, wherein in the at least one compound of formula I, m is 1, X, Y and Z are H, R¹ is H, and R² and R³ together form 3-p-menthyl.
 20. The compound according to claim 13, wherein in the at least one compound of formula I, m is 2, X is Me, Y and Z are H, R¹ is H, and R² and R³ together form 3-p-menthyl. 